Wootton David M, Popel Aleksander S, Alevriadou B Rita
Department of Biomedical Engineering, Traylor 619, The Johns Hopkins University School of Medicine, 720 Rutland Ave., Baltimore, MD 21205, USA.
Biotechnol Bioeng. 2002 Feb 15;77(4):405-19.
During thrombolytic therapy and after recanalization is achieved, reduction in the volume of mural thrombi is desirable. Mural thrombi are known to contribute to rethrombosis and reocclusion. The lysis rate of mural thrombi has been demonstrated to increase with fluid flow in different experimental models, but the mechanisms responsible are unknown. An experimental and a theoretical study were developed to determine the contribution of outer convective transport to the lysis of mural fibrin clots. Normal human plasma containing recombinant tissue-type plasminogen activator (tPA; 0.5 microg/mL) was (re)perfused over mural fibrin clots with fluorescently labeled fibrin at low arterial, arterial, or higher wall shear stresses (4, 18, or 41 dyn/cm(2), respectively) and lysis was monitored in real time. Flow accelerated lysis, but significantly only at the highest shear stress: The average lysis front velocity was 3 x 10(-5) cm/s at 41 dyn/cm(2) vs. almost half of that at the lower shear stresses. Confocal microscopy showed fibrin fibers dissolving only in a narrow region close to the surface when permeation velocity was predicted to be low. A heterogeneous transport-reaction finite element model was used to describe mural fibrinolysis. After scaling the effects of outer and inner convection, inner diffusion, and chemical reactions, a simplified inner diffusion/reaction model was used. Correlation to fibrin lysis data in purified systems dictated higher rates of plasmin(ogen) and tPA adsorption onto fibrin and a decreased catalytic rate of plasmin-mediated fibrin degradation, compared with published parameters. At each shear stress, the model predicted a temporal pattern of lysis of mural fibrin (similar to that observed experimentally), and protease accumulation in a narrow fibrin region and significant lysis inhibition by plasma alpha(2)-antiplasmin (according to the literature). Increasing outer convection accelerated mural fibrinolysis, but the model did not predict the big increase in lysis rate at the highest shear stress. At higher than arterial flows, additional mechanisms not accounted for in the current model, such as fibrin collapse at the fibrin front, may regulate the lysis of mural clots and determine the outcome of thrombolytic therapy.
在溶栓治疗期间及实现再通后，希望壁血栓体积减小。已知壁血栓会导致再血栓形成和再闭塞。在不同实验模型中，已证明壁血栓的溶解速率会随流体流动而增加，但其作用机制尚不清楚。开展了一项实验研究和一项理论研究，以确定外部对流传输对壁纤维蛋白凝块溶解的作用。将含有重组组织型纤溶酶原激活剂（tPA；0.5微克/毫升）的正常人血浆以低动脉、动脉或更高壁面剪应力（分别为4、18或41达因/平方厘米）在带有荧光标记纤维蛋白的壁纤维蛋白凝块上进行（再）灌注，并实时监测溶解情况。流动加速了溶解，但仅在最高剪应力下显著：在41达因/平方厘米时，平均溶解前沿速度为3×10⁻⁵厘米/秒，而在较低剪应力下几乎是其一半。共聚焦显微镜显示，当预测渗透速度较低时，纤维蛋白纤维仅在靠近表面的狭窄区域溶解。使用非均质传输 - 反应有限元模型来描述壁纤维蛋白溶解。在对外部和内部对流、内部扩散及化学反应的影响进行标度后，使用了简化的内部扩散/反应模型。与纯化系统中的纤维蛋白溶解数据相关分析表明，与已发表参数相比，纤溶酶（原）和tPA在纤维蛋白上的吸附速率更高，而纤溶酶介导的纤维蛋白降解催化速率降低。在每个剪应力下，该模型预测了壁纤维蛋白溶解的时间模式（与实验观察到的相似），以及蛋白酶在狭窄纤维蛋白区域的积累，并且根据文献，血浆α₂ - 抗纤溶酶对溶解有显著抑制作用。增加外部对流加速了壁纤维蛋白溶解，但该模型未预测到在最高剪应力下溶解速率的大幅增加。在高于动脉血流的情况下，当前模型未考虑的其他机制，如纤维蛋白前沿的纤维蛋白塌陷，可能会调节壁血栓的溶解并决定溶栓治疗的结果。
